Lack of a role of glutathione in cellular nonenzymatic activation of BMS-181174, a novel analogue of mitomycin C

Hong Xia, Tina Pinto, Xun Hu, Patrick J. Benson, Howard A. Zaren, Vicram Gupta, Shivendra V. Singh

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Abstract

Recent studies, using a cell-free system, have suggested that thiol- dependent nonenzymatic bioactivation may be responsible for the superior antitumor activity of the mitomycin C analogue BMS-181174 [N-7-[2-(4- nitrophenyldithio)ethyl]mitomycin CI when compared to the parent compound. If operational in tumor cells, this pathway could have enormous clinical implications since tumor cell resistance to a variety of anticancer agents is often associated with increased glutathione (GSH) levels and BMS-181174 may be used to reverse this mechanism of resistance. The present study was undertaken to determine the role of GSH in cellular activation of BMS-181174 using a pair of well-characterized human bladder cancer cells (J82 and SCaBER) as a model. A 20-h pretreatment of J82 and SCaBER cells with a nontoxic concentration of D,L-buthionine-S,R-sulfoximine (BSO) caused about 80-88% reduction in cellular GSH levels. Surprisingly, the sensitivity of both cells to BMS-181174 was increased, not reduced, by BSO-induced GSH depletion. On the other hand, the cytotoxicity of BMS-181174 was significantly reduced in both cells by a 4-h pretreatment with 1 mM GSH. Like BSO, a 4-h pretreatment with another thiol compound (cysteine) resulted in a statistically significant sensitization of both cells to BMS-181174. Cellular GSH levels were not affected in either of the cell lines by pretreatment with GSH or cysteine. In conclusion, the results of the present study argue against a role of GSH in cellular nonenzymatic activation of BMS-181174 in J82 and SCaBER cells.

Original languageEnglish (US)
Pages (from-to)3495-3498
Number of pages4
JournalCancer Research
Volume56
Issue number15
StatePublished - Aug 1 1996

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Xia, H., Pinto, T., Hu, X., Benson, P. J., Zaren, H. A., Gupta, V., & Singh, S. V. (1996). Lack of a role of glutathione in cellular nonenzymatic activation of BMS-181174, a novel analogue of mitomycin C. Cancer Research, 56(15), 3495-3498.